Antiinflammatory properties of PAH drugs

Abstract

In patients suffering from pulmonary arterial hypertension (PAH) elevated levels of monocyte-derived cytokines have been described in early stage of disease. Beside vasodilatory potential, specific anti-inflammatory activities of current PAH drugs might contribute to their therapeutic efficacy. We studied the anti-inflammatory properties of different classes of PAH drugs in human monocytes. CD14+ monocytes were isolated from blood taken from healthy donors with their informed consent. Cultured cells were stimulated with different concentrations of macitentan, riociguat, prostacyclin I2 analogues (iloprost, treprostinil) and the selective prostacyclin receptor agonist selexipag w/o LPS. For blocking experiments cells were pretreated with an inhibitor for the NfκB as well as the MAPK pathway, followed by incubation with LPS and the medications. The IL-6, IL-10 and TNF-α concentration of cell supernatants were measured with a commercially available ELISA based assay system. Only monocytes stimulated with iloprost or treprostinil showed a significant reduction of TNF-α, but no effect on the IL-6 and IL-10 release. The effect of treprostinil compared to iloprost was much stronger. The addition of the MAPK or NFκB inhibitor could further suppress the LPS-induced TNF-α expression. TNF-alpha suppression by prostacyclines has been described in various cell types and disease models. The detailed interaction between the cyclooxygenase system and the TLR-4 pathway still has to be elucidated. We show that PGI2 analogues suppress LPS induced TNF-α expression in monocytes via the MAPK and NFκB pathway, but in an IP receptor independent manner. This observation suggests a specific anti-inflammatory class effect of prostacyclin analogues in PAH therapy.